Poxviruses comprise a large family of complex DNA viruses that have vertebrate and invertebrate hosts. Two poxviruses, variola virus and molluscum contagiosum virus, are specific human pathogens. Variola virus was the cause of smallpox until the latter was eradicated but is still feared because of potential use a biological weapon. Molluscum contagiosum virus causes benign skin lesions in immunocompetent infants and a more severe and widespread disease in immunodeficient adults. In addition, several animal poxviruses can be transmitted to humans as zoonosis. The most serious of these is monkeypox, which has an estimated human mortality of 1 to 10%. The poxviruses express a large number of host immune evasion genes that contribute to virulence. The purpose of this project is to increase our understanding of poxvirus pathogenesis and the basis for immunity to poxviruses. Human genome-wide RNAi screens were conducted to determine host factors that impact poxvirus replication.